Amide compounds

ABSTRACT

The present invention is a compound and pharmaceutical composition comprising a compound of formula (I):wherein R&lt;1 &gt;is a 4-(lower) alkyl-imidazol-1-yl or a 4,5-di(lower) alkyl-imidazol-1-yl group, R&lt;2 &gt;is a hydrogen atom or a lower alkyl group, and R&lt;3 &gt;is a fluorenyl group. The compound of formula (I) includes pharmaceutically acceptable salts: The compound of formula (I) and salts thereof have 5-HT antagonism activity.

TECHNICAL FIELD

The present invention relates to novel amide compounds and saltsthereof. More particularly, it relates to novel amide compounds andsalts thereof which have pharmacological activities such as5-hydroxytryptarine (5-HT) antagonism and the like.

Said amide compounds and their salts are useful as a 5HT antagonist fortreating or preventing central nervous system (CNS) disorders such asanxiety, depression, obsessive compulsive disorders, migraine,.anorexia,Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawalfrom drug abuse (e.g., with cocaine, ethanol, nicotine andbenzodiazepines), schizophrenia, and also disorders associated withspinal trauma and/or head injury such as hydrocephalus in human beingand animals.

BACKGROUND ART

With regard to the state of the art in this field, for example, thefollowing amide compounds are disclosed in Japanese Patent Kokai No. Hei11(1999)-130750.

wherein R¹ is quinolyl, quinazolinyl, isoquinolyl or pyridyl group, R³is phenyl, cyclo(lower)alkyl, indolyl, lower alkyl-indazolyl or2,3-dihydroindolyl group, Y is single bond, lower alkylene or loweralkenylene group, and A is lower alkylene group.

DISCLOSURE OF INVENTION

As a result of an extensive study, the inventors of the presentinvention found some amide compounds which have strong pharmacologicalactivities.

The amide compounds of the present invention are novel and can berepresented by the formula (I):

wherein

R¹ is an N-containing heterocyclic group selected from an imidazolyl, atriazolyl, a pyridyl, a pyridazinyl, a pyrimidinyl and a pyrazinylgroup, each of which may be substituted with one or more lower alkylgroups,

R² is a hydrogen atom or a lower alkyl group, and

R³ is a phenyl group substituted with thienyl or halophenyl; a thienylgroup substituted with thienyl, phenyl or halophenyl; a pyrrolyl groupsubstituted with phenyl; a thiazolyl group substituted with phenyl; anindolyl group substituted with lower alkyl and/or halo(lower)alkyl; afluorenyl group; or a carbazolyl group, provided that

(1) the imidazolyl group for R₁ is substituted with one or more alkylgroups, when R³ is a phenyl group substituted thienyl; an indolyl groupsubstituted with lower alkyl; or carbazolyl group,

(2) the imidazolyl group for R¹ is substituted with two lower alkylgroups, when R³ is a phenyl group substituted with halophenyl, or

(3) R¹ is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, a 4-(loweralkyl)-imidazol-1-yl or a 4,5-di(power alkyl)-imidazol-1-yl group, whenR³ is fluorenyl group.

Suitable salts of the compounds (I) are conventional non-toxicpharmaceutically acceptable salts and may include salts with inorganicbases, for example, alkali metals (e.g. sodium or potassium), alkalineearth metals (e.g. calcium or magnesium) or ammonia; salts with organicbases, for example, organic amines (e.g. triethylamine, pyridine,picoline, ethanolamine, triethanolamine, dicyclohexylamine orN,N′-dibenzylethylenediamine); inorganic acid addition salts (e.g.hydrochloride, hydrobromide, hydriodide, sulfate or phosphate); organiccarboxylic or sulfonic acid addition salts (e.g. formate, acetate,trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonateor p-toluenesulfonate); salts with basic or acidic amino acids (e.g.arginine, aspartate or glutamate); and the like, and preferable examplesthereof are the inorganic or organic acid addition salts.

According to the present invention, the object compounds (I) can beprepared by the following process:

wherein R¹, R² and R³ are each as defined above.

In the above and subsequent descriptions of the present. specification,suitable examples and illustrations of the various definitions which thepresent invention include within the scope are explained in detail inthe following.

The term “lower” is intended to mean 1 to 6 carbon atoms, preferably 1to 4 carbon atoms, unless otherwise indicated.

Suitable lower alkyl groups and lower alkyl moieties in thehalo(lower)alkyl groups may include straight or branched ones, having 1to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl,t-butyl, pentyl and hexyl, and preferably the ones having 1 to 4 carbonatom(s), among which the most preferred one is methyl.

Suitable halo(lower)alkyl groups may include lower alkyl groupssubstituted with one or more halogen atoms such as fluoromethyl,fluoroethyl, fluoropropyl, trifluoromethyl, chloromethyl,dichloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl,bromopropyl, iodomethyl, iodoethyl, iodopropyl, and the like.

Suitable halophenyl groups may include fluorophenyl, difluorophenyl,chlorophenyl, dichlorophenyl, trichlorophenyl, bromophenyl,dibromophenyl, tribromophenyl, iodophenyl, and the like.

When imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl orpyrazinyl groups for R¹ is substituted with two or more lower alkylgroups, said lower alkyl groups may be the same or different from eachother.

And also, when indolyl group for R³ is substituted with two or morelower alkyl groups and/or two or more halo(lower)alkyl groups, saidlower alkyl groups and halo(lower)alkyl groups may be the same ordifferent from each other.

The process for preparing the object compounds (I) is explained indetail in the following.

The object compound (I) and its salt can be prepared by reacting acompound (II) or its reactive derivative at the amino group or a saltthereof with a compound (III) or its reactive derivative at the carboxygroup or a salt thereof.

Suitable reactive derivatives at the amino group of the compound (II)may include Schiff's base type imine or its tautomeric enamine typeisomer formed by the reaction of the compound (II) with a carbonylcompound such as aldehyde, ketone or the like; a silyl derivative formedby the reaction of the compound (II) with a silyl compound such asbis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide,bis(trimethylsilyl)urea or the like; a derivative formed by the reactionof a compound (II) with phosphorus trichloride or phosgene, and thelike.

Suitable salts of the compound (II) and its reactive derivative can bereferred to those as exemplified for the compound(l).

Suitable reactive derivatives at the carboxy group of the compound (III)may include the acid halides, acid anhydrides, activated amides,activated esters and the like.

Suitable examples of such reactive derivatives may be the acid chloride;the acid azide; the mixed acid anhydride with an acid such assubstituted phosphoric acid [e.g. dialkylphosphoric acid,phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acidor halogenated phosphoric acid], dialkylphosphorous acid, sulfurousacid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g.methanesulfonic acid], aliphatic carboxylic acid [e.g. acetic acid,propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoicacid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid] oraromatic carboxylic acid [e.g. benzoic acid]; symmetrical acidanhydride; activated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole or tetrazole; or activated ester [e.g.cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl[(CH₃)₂N*=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyranyl ester, pyridyl ester, piperidyl ester or 8-quinolyl thioester],or ester with an N-hydroxy compound [e.g. N,N-dimethylhydroxylamine,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinide, N-hydroxyphthaimide or1-hydroxy-1H-benzotriazole], and the like.

The reactive derivative can optionally be selected from the aboveaccording to the kind of the compound (III) to be used.

Suitable salts of the compound (III) and its reactive derivative may bethe base salts such as alkali metal salts [e.g. sodium salt or potassiumsalt], alkaline earth metal salts [e.g. calcium salt or magnesium salt],ammonium salts, organic base salts [e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine saltor N,N′-dibenzylethylenediamine salt], or the like, and acid additionsalts as exemplified for the compound (I).

The reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g. methanol or ethanol], acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction,or a mixture thereof.

In this reaction, when the compound (III) is used in a free acid form orits salt form, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N′-dicyclohexylcarbodiimide;N-cyclohexyl-N′-morpholinoethylcarbodiimide;N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide;N-N′-diethylcarbodiiide, N,N′-diisopropylcarbodiimide;N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide;N,N′-carbonylbis-(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylixine; ethoxyacetylene;1-alkoxy-1-chloroethylene; triallyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride;oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate,isopropyl chloroformate, etc.]; triphenylphosphine;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)-isoxazolium hydroxide intramolecular salt;benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorusoxychloride or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal bicarbonate, tri(lower)alkylamine,pyridine, N-(lower) alkylmorpholine, N,N-di(lower)alkylbenzylamine orthe like,

The reaction is usually carried out under cooling to warming, althoughthe reaction temperature is not critical.

The object compound (I) of the present invention can be isolated andpurified in a conventional manner, for example extraction,precipitation, fractional crystallization, recrystallization,chromatography and the like.

The object compound (I) thus obtained can be converted to itscorresponding salt by the conventional method.

The object compound (I) and salts thereof may include solvates [e.g.,enclosure compound (e.g., hydrate, etc.)].

Among the starting compounds (II) and (III), novel compounds can beprepared by the method described in the following Examples or similarmethod thereto.

In order to exhibit the usefulness of the present invention, theactivities of the compounds (I) are shown in the following.

Test Method.

[³H]-mesulergine Binding

The affinity of the test drugs for the 5-HT_(2c) binding site can bedetermined by assessing their ability to displace [³H]-mesulergine inthe rat prefrontal cortex. The method employed was similar to that ofPazos et al, 1984.

The membrane suspension (500 μl) was incubated with [³H]-mesulergine (1nM) in Tris HCl buffer containing CaCl₂4 mM and ascorbic acid 0.1 % (pH7.4) at 37° C. for 30 minutes. Non-specific binding was measured in thepresence of mianserin (1 μM). 30 nM spiperone was used to preventbinding to 5-HT_(2A) sites. Test drugs (10⁻⁶ M) were added in a volumeof 100 μl. The total assay volume was 1000 μl. Incubation was stopped byrapid filtration using a Brandel cell harvester and radioactivitymeasured by scintillation counting.

The IC₅₀ values were determined using a four parameter logistic program(DeLean 1978) and the phi (the negative logarithm of the inhibitionconstant) calculated from the Cheng Prusoff equation where:${Ki} = \frac{{IC}_{50}}{1 + {C\text{/}{Kd}}}$ $\begin{matrix}\begin{matrix}{{Ki} = \text{inhibition~~constant}} \\{C = {\text{concentration~~of~~}\text{[}^{\text{3}}\text{H}\text{]}\text{-mesulergine}}}\end{matrix} \\{{Kd} = {\text{affinity~~of~~mesulergine~~for~~}5\text{-HT}_{2c}\text{~~binding~~site.}}}\end{matrix}$

Test Compounds:

(1) N-(1-Methyl-1H-indol-5-yl)-N′-(3-pyridyl)urea (reference compound)

(2) N-(3-(yridin-3-yl)phenyl)-9H-fluorene-1-carboxamide (Example 1)

(3) N-(3-(pyrimidin-5-yl)phenyl)-9H-fluorene-1-carboxamide (Example 2)

(4) N-(3-(pyridazin-4-yl)phenyl)-9H-fluorene-1-carboxamide (Example 6)

Test Result:

Inhibition Compound (%) (1) 21 (2) 74 (3) 92 (4) 64

As shown in above, the object compounds (I) of the present inventionexhibit pharmacological activities such as 5-HT antagonism, especially,5-HT_(2c)antagonism, and therefore are useful as 5-HT antagonist fortreating or preventing central nervous system (CNS) disorders such asanxiety, depression, obsessive compulsive disorders, migraine, anorexia,Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawalfrom drug abuse (e.g., with cocaine, ethanol, nicotine and benzodiapines), schizophrenia, and also disorders associated with spinal traumaand/or head injury such as hydrocephalus, and the like.

For therapeutic or preventive administration, the object compounds (I)of the present invention are used in a form of conventionalpharmaceutical preparation which contains said compound as an activeingredient, in admixture with pharmaceutically acceptable carriers suchas an organic or inorganic solid or liquid excipient which is suitablefor oral, parenteral and external administration. The pharmaceuticalpreparations may be in a solid form such as tablet, granule, powder orcapsule, or in a liquid form such as solution, suspension, syrup,emulsion or lemonade.

If needed, there may be included in the above preparations auxliarysubstances, stabilizing agents, wetting agents and other commonly usedadditives such as lactose, citric acid, tartaric acid, stearic acid,magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin,agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol andthe like.

While the dosage of the compound (I) may vary from and also depend uponthe age, conditions of the patient, kind of diseases or conditions, kindof the compound (I) to be applied, etc., in general, 0.01-500 mg of thecompound (I) may be administered to a patient per day.

An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg,20 mg, 50 mg, 100 mg of the compound (I) may be used in treating thediseases.

The following Examples are given for illustrating the present invention,but it is to be noted that the scope of the present invention is notlimited by these Examples.

BEST MODE FOR CARRYING OUT THE INVENTION

The following Examples are given only for the purpose of illustratingthe present invention in more detail.

EXAMPLE 1

To a suspension of 3-pyridin-3-yl)aniline (0.17 g) and pyridine (0.24ml) in dichloromethane (3 ml) was dropwise added a solution of thefluorene-1-carbonyl chloride (0.23 g) in dichloromethane (2 ml) followedby stirring for 2 hours. The mixture was diluted with dichloromethaneand washed with an aqueous solution of sodium hydrogen carbonate andbrine. The separated organic layer was dried over sodium sulfate andevaporated under reduced pressure. The residue was purified by a silicagel column chromatography eluting with 2% methanol in dichloromethane togive N-(3-(pyridin-3-yl)phenyl)-9H-fluorene-1-carboxamide (0.317 g,87.6%).

NMR (DMSO-d₆, δ):4.23 (2H, s), 7.3-b 7.7 (7H, m), 7.78 (1H, d, J=7.7Hz), 7.8-8.1 (4H, m), 8.18 (1H, s), 8.60 (1H, d, J=4.8 Hz), 8.88 (1H,s), 10.47 (1H, s) APCI-Mass m/z: 363 (M⁺+1).

EXAMPLE 2

To a suspension of 3-(pyrimidin-5-yl)aniline (0. 17g) and pyridine (0.24ml) in dichloromethane (3 ml) was dropwise added a solution of thefluorene-1-carbonyl chloride (0.23 g) in dichloromethane (5 ml) followedby stirring for 2 hours. The mixture was diluted with dichloromethaneand washed with an aqueous solution of sodium hydrogen carbonate andbrine. The separated organic layer was dried over sodium sulfate andevaporated. The residue was purified by a silica gel columnchromatography eluting with 2% methanol in dichloromethane to giveN-[3-(pyrimidin-5-yl)phenyl]fluorene-1-carboxamide (0.222 g, 61.2 %).

NMR PMSO-d₆, δ): 4.23 (2H, s), 7.3-7.5 (2H, m), 7.5-7.7 (4H, m), 7.78(1H, d, J=8.0 Hz), 7.8-8.1 (2H, m), 8.13 (1H, d, J 7.7 Hz), 8.21 (1H,s), 9.12 (2H, s), 9.23 (1H. s), 10.51 (1H, s) APCI-Mass m/z: 364 (M⁺+1).

EXAMPLE 3

To a suspension of 9H-carbazole-1-carboxylic acid (106 mg) and1-hydroxybenzotriazole (81 mg) in dichloromethane (2 ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg) andthe mixture was stirred for 15 minutes. After adding3-(1,2-dimethylimidazol-5-yl)aniline (94 mg) and 4-dimethylaminopyridine(92 mg), the mixture was stirred for 60 hours. The residue wasevaporated under reduced pressure and purified by a silica gel columnchromatography eluting with 2% methanol in dichloromethane to giveN-[3-(2,3-dimethyl-3H-imidazol-4-yl)-phenyl]-9H-carbazole-1-carboxamide(101 mg, 53.2%).

NMR PMSO-d₆, δ): 2.37 (3H, s), 3.59 (3H, s), 6.90 (1H, s), 7.2-7.6 (5H,m), 7.71 (1H, d, J=8.0 Hz), 7.89 (1H, d, J=8.2 Hz), 7.96 (1H, s), 8.11(1H, d, J=7.4 Hz), 8.18 (1H, d, J=7.7 Hz), 8.38 (1H, d, J=7.7 Hz), 10.47(1H, s), 11.49 (1H, s) APCI-Mass m/z; 381 (M⁺1).

Preparation 4(1)

To a suspension of 3,6-dichloropyridazine (2.98 g), 3-nitrophenylboronicacid (1.67 g) and tetralis(triphenylphosphine)-palladium (578 mg) in1,2-dimethoxyethane (30 ml) was added an aqueous solution of sodiumcarbonate (2M, 15 ml), and the mixture was stirred at 80° C. for 3hours. The mixture was diluted with ethyl acetate, and then washed withwater and brine. The organic layer was dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified by a silicagel column chromatography eluting with 30% ethyl acetate in n-hexane togive 3-chloro-6-(3-nitro-phenyl)-pyridazine (0.246 g, 10.4%).

NMR (DMSO-d₆, δ): 7.88 (1H, t, J=8.1 Hz), 8.13 (1H, d, J=9.0 Hz), 8.41(1H, dt, J=6.8 Hz, 1.2 Hz), 8.54 (1H, d, J=9.0 Hz), 8.6-8.8 (1 H,m),8.97 (1H, t, J=1.2 Hz) APCI-Mass m/z : 236 (M⁺+1).

Preparation 4(2)

A suspension of 3-chloro6-(3-nitro-phenyl)pyridazine (0.34 g) intetrhydrofuran (5 ml) and ethanol (5 ml) was hydrogenated over palladiumon carbon (10% w/w, 50% wet, 100 mg) under hydrogen atmosphere for 10hours. The catalyst was filtered off and the filtrate was evaporatedunder reduced pressure. The residue was diluted with ethyl acetate andan aqueous solution of sodium hydrogen carbonate. The separated organiclayer was washed with brine, dried over magnesium sulfate and evaporatedunder reduced pressure to give 3-pyridazin-3-yl-phenylamine (155 mg,62.8%).

NMR (DMSO-d₆, δ): 5.29 (2H, broad s), 6.72 (1H, t, J=2.8 Hz), 7.1-8.0(4H, ml, 8.04 (1H, d, J=8.6 Hz), 9.16 (1H, dd, J=5.0 Hz, 1.6 Hz)APCI-Mass m/z: 172 (M⁺+1).

EXAMPLE 4

To a suspension of 1-fluorenecarboxylic acid (184 mg) and oxalylchloride (0.2 ml) in dichloromethane (4 ml) was addedN,N-dimethylformamide (0.01 ml), and the mixture was stirred for 2hours. The resultant solution was evaporated to give a crude acidchloride. To a suspension of 3-pyridazin-3-yl-phenylamine (150 mg) andpyridine (0.21 ml) in dichloromethane (2 ml) was dropwise added asolution of the acid chloride obtained above in dichloromethane. (5 ml)followed by stirring for an hour. The mixture was diluted withdichloromethane and washed with an aqueous solution of sodium hydrogencarbonate and brine. The separated organic layer was dried over sodiumsulfate and evaporated under reduced pressure. The residue was purifiedby a silica gel column chromatography eluting with 2% methanol indichloromethane to giveN-(3-(pyridazin-3-yl)phenyl)-9H-fluorene-1-carboxamide (44 mg, 13.8%).

NMR (DMSO-d₆, δ): 4.24 (2H, s). 7.3-7.5(2H, m), 7.5-7.7 (3H, m), 7.7-7.9(3H, m), 7.99 (1H, dd, J=7.0 Hz, 1.8 Hz), 8.1-8.3 (2H, m), 8.70 (1H, t,J=3.6 Hz), 9.24 (1H, dd, J=4.9 Hz, 1.5 Hz), 10.54 (1H, s) APCI-Mass m/z:364 (M⁺+1).

Preparation 5(1)

To a suspension of 2-chloropyrazine (1.14 g), 3-nitrophenylboronic acid(2.00 g) and tetrakis(triphenylphosphine)-palladium (346 mg) in1,2-dimethoxyethane (30 ml) was added an aqueous solution of sodiumcarbonate (2M, 12 ml) followed by stirring at 80° C. for 18 hours. Themixture was diluted with dichloromethane and washed with water andbrine. The organic layer was dried over magnesium sulfate and evaporatedunder reduced pressure. The residue was triturated with methanol andcollected by filtration. The obtained product was washed with methanoland diisopropyl ether and dried to give 2-(3-nitrophenyl)pyrazine (1.78g, 88.6%).

NMR (CDCl, δ): 7.26 (1H, s), 7.67 (1H, t, J=8.0 Hz), 8.36 (1H, dt, J=7.7Hz, 1.5 Hz), 8.63 (1H, d, J=2.4 Hz), 8.70 (1H, t, J=4.0 Hz), 8.93 (1H,t, J=4.0 Hz), 9.13 (1H, t, J=1.5 Hz) APCI-Mass m/z: 202 (M⁺+1).

Preparation 5(2)

A suspension of 2-(3-nitrophenyl)pyrazine (500 mg) in tetrahydrofuran (5ml) and ethanol (5 ml) was hydrogenated over palladium on carbon (10%w/w, 50% wet, 200 mg) under hydrogen atmosphere for 6 hours. Thecatalyst was filtered off and the filtrate was evaporated. The residuewas crystallized from dichloromethanediisopropyl ether to give3-(pyrazin-2-yl)aniline (410 mg, 96.5%).

NMR (CDCl₃, δ): 3.82(2H, s), 6.81 (1H, dt, J=6.0 Hz, 1.2 Hz), 7.3-7.6(3H, m), 8.49 (1H, d, J=2.5 Hz), 8.60 (1H, t, J=1.3 Hz), 9.00 (1H, d,J=1.5 Hz) APCI-Mass m/z: 171 (M⁺+1).

EXAMPLE 5

To a suspension of 3-(pyrazin-2-yl)aniline (0.12g) and pyridine (0.17ml)in dichloromethane (3ml) was dropwise added a solution of thefluorene-1-carbonyl chloride (0.16 g) in dichloromethane (3 ml) followedby stirring for 2 hours. The mixture was diluted with dichloromethaneand washed with an aqueous solution of sodium hydrogen carbonate andbrine. The separated organic layer was dried over sodium sulfate andevaporated under reduced pressure. The residue was purified by a silicagel column chromatography eluting with 2% methanol in dichloromethane togive N-(3-(pyrazin-2-yl)phenyl)-9H-fluorene-1-carboxamide (0.193 g;76.0%).

NMR (DMSO-d₆, δ): 4.24 (2H, s), 7.3-7.7 (5H, m), 7.79 (1H, d, J=7.6 Hz),7.8-8.1 (3H, m), 8.13 (1H, d, J=6.8 Hz), 8.68.7 (2H, m), 8.76 (1H, t,J=1.2 Hz), 9.23 (1H, d, J=1.5 Hz), 10.52 (1H, s) APCI-Mass m/z: 364 (M³⁰+1).

Preparation 6(1)

A suspension of 3-nitrobenzyl cyanide (1.62 g), glyoxylic acidmonohydrate (1.38 g) and potassium carbonate (3.59 g) in methanol (20ml) was stirred for 5 hours. The precipitate was collected byfiltration, washed with dichloromethane and dried. The precipitate wassuspended in water and stirred for an hour. The insoluble material wascollected by filtration and dried to give3-cyano-3-(3-nitro-phenyl)-acrylic acid potassium salt (2.18 g, 85.2%).

ESI-Mass m/z: 217 (M−K⁺) NMR (DMSO-d₆, δ): 7.36 (1H, s), 7.73 (1H, t,J=8.0 Hz), 8.10 (1H, d, J=7.9 Hz), 8.24 (1H, d, J=7.9Hz), 8.62 (lH, s)

Preparation 6(2)

To a suspension of.3-cyano-3-(3-nitro-phenyl)-acrylic acid potassiumsalt (1.28 g) in formic acid (10 ml) and water (1 ml) was added sulfuricacid (1 ml), and the mixture was refluxed for 3 hours. After cooling,the mixte was poured into water. The resulting precipitate was collectedby filtration and dried to give 3-(3-nitrophenyl)-furan-2,5-dione(0.69g).

NMR (CDCl₃, δ): 7.24 (1H, d, J=8.9 Hz), 7.76 (1H, d, J=8.1 Hz), 8.3-8.5(2H, m), 8.81 (1H,s) APCI-Mass m/z: 220 (M⁺+1).

Preparation 6(3)

To a suspension of 3-(3-nitro-phenyl)-f ran-2,5-dione (673 mg) in aceticacid (7 ml) was added hydrazine hydrate (0.18 ml), and the mixture wasrefluxed for S hours. The mixture was poured into water. The resultingprecipitate was collected by filtration and dried to give4-(3-nitro-phenyl)-1,2-dihydro-pyridazine-3,6-dione (0.68 g, 95.0%). NMR(0MSO-d₆, δ): 7.43 (1H, s), 7.6˜8.4 (3H, m), 8.81 (1H, s), 11.04 (1H,broad s), 12.31 (1H, broad s) APCI-Mass m/z: 234 (M⁺+1).

Preparation 6(4)

A suspension of 4-(3nitro-phenyl)-1,2-dihydropyridazine-3,6-dione (668mg) in phosphorus oxychloride (6 ml) was refluxed for 2 hours. Themixture was concentrated under reduced pressure and diluted with ethylacetate. The solution was washed with an aqueous solution of sodiumhydrogen carbonate and brine and dried over magnesium sulfate. Theorganic layer was evaporated under reduced pressure. The residue waspurified by a silica gel column chromatography eluting withdichloromethane to give 3,6-dichloro-4-(3-nitro-phenyl)pyridazine (385mg, 49.9%). NMR (CDCl₃, δ): 7.26(1H, s), 7.57 (1H, s), 7.76 (1H, t,J=8.1 Hz), 7.86 (1H d, J=7.9 Hz), 8.4-8.6 (2H, m) APCI-Mass m/z: 270(M⁺+1).

Preparation 6(5)

A suspension of 3,6dichloro4-(3-nitro-phenyl)pyridazine (0.19 g) andsodium hydrogen carbonate (147 mg) in tetrahydrofuran (2 ml) and ethanol(5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 100mg) under hydrogen atmosphere for 3 hours. The catalyst was filteredoff, and the filtrate was evaporated. The residue was diluted with ethylacetate and an aqueous solution of sodium hydrogen carbonate. Theseparated organic layer was washed with brine and dried over potassiumcarbonate. The organic layer was evaporated under reduced pressure togive 3-(pyridazin-4-yl)phenylamine (106 mg, 88.3%).

NMR PMSO-d₆, δ): 5.35 (2H, broad s), 6.72 (1H, t, J=7.6 Hz), 7.0-7.2(2H, m), 7.20 (1H, t, J=8.0 Hz), 7.85 (1H, dd, J=5.6 Hz, 2.4 Hz), 9.23(H, d, J=5.6 Hz), 9.49 (1H, s) APCI-Mass m/z: 172 (M⁺+1).

EXAMPLE 6

To a suspension of 1-fluorenecarboxylic acid (120 mg) and oxalylchloride (0.12 ml) in dichloromethane (2.5 ml) was addedN,N-dimethylformamide (0.01 ml) and the mixture was stirred for 2 hours.The resultant solution was evaporated to give a crude acid chloride. Toa suspension of 3-(pyridazin-4-yl)phenylamine (98 mg) and pyridine (0.14ml) in dichloromethane (2 ml) was dropwise added a solution of the acidchloride obtained above in dichloromethane (5 ml), and the mixture wasstirred for an hour. The mixture was diluted with dichloromethane andwashed with an aqueous solution of sodium hydrogen carbonate and brine.The separated organic layer was dried over sodium sulfate and evaporatedunder reduced pressure. The residue was purified by a silica gel columnchromatography eluting with 2% methanol in dichloromethane to giveN-(3-(pyridazin-4-yl)-phenyl)-9H-fluorene-1-carboxamide (133 mg, 63.9%)

NMR (DMSO-d₆, δ): 4.23 (2H, s), 7.3-7.7 (6H, m), 7.79 (1H, d, J=7.0 Hz),7.9-8.1 (3H, m), 8.14 (1H, d, J=6.9 Hz), 8.34 (1H, s), 9.32 (1H, d,J=5.5 Hz), 9.60(1H, s), 10.56(1H, s) APCI-Mass m/z: 364 (M⁺+1).

Preparation 7

To a solution of 2-(3-methoxycarbonylphenyl)thiophene (1.29 g) inmethanol (15 ml) and tetrahydrofuran (5 ml) was added an aqueoussolution of sodium hydroxide (1N, 8.87 ml) followed by stirring for 2hours at 60° C. To the mixture was added hydrochloric acid (1N, 10 ml).The resulting precipitate was collected by filtration and dried to give2-(3-carboxyphenyl)thiophene (1.13 g, 93.4%).

NMR (DMSO-d₆, δ): 7.17 (1H, t, J=4.4 Hz), 7.5-7.7(3H, m), 7.87 (1H, d,J=7.8 Hz), 7.93 (1H, d, J=7.8 Hz), 8.15 (1H, s), 13.19 (1H, broad s)ESI-Mass m/z: 203 (M⁺−1).

EXAMPLE 7

To a suspension of 3-(2-thienyl)benzoic acid (102 mg) and oxalylchloride (0.2 ml) in dichloromethane (2 ml) was addedN,N-dimethylformamide (0.01 ml), and the mixture was stirred for anhour. The resultant solution was evaporated to give a crude acidchloride. To a suspension of 3-(1,2-dimethylimidazol-5-yl)aniline (94mg) and pyridine (0.12 ml) in dichloromethane (2 ml) was dropwise addeda solution of the acid chloride obtained above in dichloromethane (2ml), and the mixture was stirred for 12 hours. The mixture was dilutedwith dichloromethane and washed with an aqueous solution of sodiumhydrogen carbonate and brine. The separated organic layer was dried oversodium sulfate and evaporated under reduced pressure. The residue waspurified with a silica gel column chromatography eluting with 3%methanol in dichloromethane to give N-[3-(2,3-dimethyl-3H-idazol-4-yl)-phenyl]-3-(thiophen-2-yl)benzamide (140 mg, 74.9%).

NMR (DMSO-d₆, δ): 2.36 (3H,s), 3.59 (3H, s), 6.89 (1H, s), 7.1-7.3 (2H,m), 7.44 (1H, t, J=7.9 Hz), 7.6-7.8 (3H, m), 7.79 (1H, d, J=8.0 Hz),7.8-8.0 (3H, m), 8.19 (1H, s), 10.45 (1H, s) APCI-Mass m/z: 374 (M⁺+1).

EXAMPLE 8

To a suspension of 9H-carbazole-1-carboxylic acid (422 mg) and1-hydroxybenzotriazole (324 mg) in dichloromethane (10 ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (575 mg),and the mixture was stirred for 15 minutes. After adding3-(pyrimidin-5-yl)aniline (360 mg) and 4-dimethylaminopyridine (367 mg),the mixture was stirred for 48 hours. The residue was evaporated underreduced pressure and purified by a silica gel column chromatographyeluting with 2% methanol in dichloromethane to give N-(3-idin-5-yl)-phenyl)-9H-carbazole-1-carboxamide (314 mg, 43.1%).

NMR (DMSO-d₆, δ): 7.20(1H, t, J=7.4 Hz), 7.33 (1H, t, J=7.7 Hz), 7.42(1H, t, J=7.6 Hz), 7.58 (2H, d, J=5.1 Hz), 7.72 (1H, d, J=8.0 Hz),7.9-8.1 (1H, m),8.17 (2H, dd, J=7.4 Hz, 4.0 HZ), 8.35 (1H, 5), 8.39 (1H,d, J=7.5Hz), 9.15 (2H, s), 9.23 (1H, s), 10.56 (1H, s), 11.54 (1H, s)APCI-Mass m/z: 365 (M⁺+1).

EXAMPLE 9

To a suspension of 9H-carbazole-1-carboxylic acid (148 mg) and1-hydroxybenzothiazole (114 mg) in dichloromethane (3 ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (201 mg) andthe mixture was stirred for 15 minutes. After adding3-(1,2,4-triazol-1-yl)aniline (123 mg) and 4-dimethylaminopyridine (128mg), the mixture was stirred for 24 hours. The mixture was evaporatedunder reduced pressure and purified by a silica gel columnchromatography eluting with 2% methanol in dichloromethane to giveN-[3-(1,2,4-triazol-1-yl)-phenyl]-9H-carbazole-1-carboxamide (103 mg,41.5%).

NMR (DMSO-d₆, δ): 7.20(1H, t, J=7.3 Hz), 7.32 (1H, t, J=7.5 Hz), 7.42(1H, t, J=7.3 Hz), 7.5-7.7 (2H, m), 7.73 (1H, d, J=8.2 Hz), 7.86 (1H, d,J=7.3 Hz), 8.1-8.3 (2H, m), 8.28 (1H, s), 8.40 (1H, d, J=7.5 Hz), 8.61(1H, s), 9.30 (1H, s), 10.64 (1H, s), 11.57 (1H, s) APCI-Mass m/z: 354(M⁺+1).

Preparation 10(1)

To a suspension of 2-bromo-5-methoxycarbonylthiophene (1.11 g) andphenylboronic acid (0.79 g) and tetrakis(triphenylphosphine)-palladium(289 mg) in 1,2-dimethoxyethane (10 ml) was added an aqueous solution ofsodium carbonate (2M, 6.5 ml) followed by stirring at 80° C. for 18hours. The mixture was diluted with dichloromethane and washed withwater and brine. The mixture was dried over magnesium sulfate andevaporated under reduced pressure. The residue was triturated withmethanol. The resulting precipitate was collected by filtration, washedwith methanol and diisopropyl ether and dried to give2-methoxycarbonyl-5-phenylthiophene (918 mg, 84.2%).

NMR (CDCl₃, δ): 3.84 (3H, s), 7.4-7.6 (3H, m), 7.62 (1H, d, J=4.0 HZ),7.7-7.9 (2H, m), 7.81 (1H, d, J=4.0 Hz) APCI-Mass m/z : 219 (M⁺+1).

Preparation 10(2)

To a solution of 2-methoxycarbonyl-5-phenylthiophene (437 mg) inmethanol (5 ml) and tetrahydrofuran (5 ml) was added an aqueous solutionof sodium hydroxide (IN, 3 ml) followed by stirring for 2 hours. To themixture was added hydrochloric acid (IN, 5 ml). The precipitate wascollected by filtration and dried to give 5-phenylthiophene-2-carboxylicacid (397 mg, 97.1%).

NMR (PMSO-d₆, δ): 7.3-7.5 (3H, m), 7.58 1(1H, d, J=3.9 Hz), 7.6-7.8 (3H,m), 13.15 (1H, broad s) ESI-Mass m/z: 203 (M⁺−1).

EXAMPLE 10

To a suspension of 5-phenylthiophene-2-carboxylic acid (102 mg) andoxalyl chloride (0.2 ml) in dichloromethane (2 ml) was addedN,N-dimethylformamide (0.01 ml), and the mixture was stirred for anhour. The resultant solution was evaporated under reduced pressure togive a crude acid chloride. To a suspension of3-(1,2-dimethylimidazol-5-yl)aniline (94 mg) and pyridine (0.12 ml) indichloromethane (2 ml) was dropwise added a solution of the acidchloride obtained above in dichloromethane (2 ml) followed by stirringfor 12 hours. The mixture was diluted with dichloromethane and washedwith an aqueous solution of sodium hydrogen carbonate and brine. Theseparated organic layer was dried over sodium sulfate and evaporatedunder reduced pressure. The residue was purified by a silica gel columnchromatography eluting with 3% methanol in dichloromethane to giveN-[3-(2,3-dimethyl-3H-imidazol4-yl)-phenyl]-5-phenyl-thiophene-2-carboxamide(155 mg, 82.9%).

NMR PMSO-d₆, δ): 2.36 (3H,s), 3.57 (3H, s), 6.89 (1H, s), 7.17 (1H, d,J=7.8 HZ), 7.4-7.6 (4H, m), 7.64 (1H, d, J=4.0 Hz), 7.7-7.9 14H, m),8.04 (1H, d, J=4.0 Hz), 10.34 (1H, s) APCI-Mass m/z: 374 (M⁺+1).

Preparation 11 (1)

To a suspension of 5-bromopyrimidine (1.59 g),4-methyl-3-nitrophenylboronic acid (2.35 g) andtetrakis(triphenylphosphine)-palladium (578 mg) in 1,2-dimethoxyethane(20 ml) was added an aqueous solution of sodium carbonate (2M, 13 ml)followed by stirring at 80° C. for 24 hours. The mixture was dilutedwith dichloromethane and washed with water and brine. The organic layerwas dried over magnesium sulfate and evaporated under reduced pressure.The residue was triturated with methanol. The resulting precipitated wascollected by filtration, washed with methanol and diisopropyl ether anddried to give 5-(4-methyl-3-nitrophenyl)-pyrimidine (918 mg, 84.2%).

NMR (CDCl3, 6): 2.56 (3H, s), 7.68 (1H, d, J=8.0 Hz), 8.10 (1H, dd,J=8.0 Hz, 1.8 Hz), 8.42 (1H, d. J=1.8 Hz), 9.23 (3H, s) APCI-Mass m/z:216 (M⁺+1).

Preparation 11 (2)

A suspension of 5-(4-methyl-3-nitrophenyl)-pyrimidine (258 mg) intetrahydrofuran (5ml) and methanol (5 ml) was hydrogenated overpalladium on carbon (10% w/w, 50% wet, 130 mg) under hydrogen atmospherefor 4 hours. The catalyst was filtered off and the filtrate wasevaporated to give 5-(3-amino4-methylphenyl)pyrimidine(410 mg, 96.5%).

NMR (CDCl₃, δ): 2.11 (3H, s), 5.05 (2H, s), 6.87 (1H, dd, J=7.6 Hz, 1.8Hz), 6.96 (1H, d, J=1.8 Hz), 7.07 (1H, d, J=7.6 Hz), 8.98 (2H, s), 9.12(1H, s) APCI-Mass m/z: 186 (M⁺+1).

EXAMPLE 11

To a suspension of 9H-carbazole-1-carboxylic acid (148 mg) and1-hydroxybenzotriazole (114 mg) in dichloromethane (3 ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiinide hydrochloride (201 mg),and the m e was stirred for 15 minutes. After adding5-(3-amino-4-methylphenyl)pyrimdine (136 mg) and 4dimethylaminopyridine(128 mg), the mixture was stirred for 24 hours. The mixture wasevaporated under reduced pressure and the residue was purified by asilica gel column chromatography eluting with 2% methanol indichloromethane to giveN-[6methyl-3-(pyrimidin-5-yl)-phenyl]-9H-carbazole-1-carboxamide (89 mg,33.6%).

NMR (DMSO-d₆, δ): 2.40 (3H, s), 7.20(1H, t, J=7.4 Hz), 7.32 (1H, t,J=7.6 Hz), 7.4-7.6 (2H, m), 7.6-7.8 (2H, m), 7.96 (1H, s), 8.17 (2H, d,J=77 Hz), 8.39 (1H, d, J=7.6 Hz),9.17 (2H, s), 9.19 (1H, s), 10.19 (1H,s), 11.46 (1H, s) APCI-Mass m/z: 379 (M⁺+1).

EXAMPLE 19

To a suspension of 2-trifluoromethyl-3-methylindole-7-carboxylic acid(122 mg) and 3-(1,2-dimethyiimldazol-5-yl)aniline (94 mg) indichloromethane (3 ml) were added1-ethyl-3-(3-dimethylamiopropyl)carbodiimide hydrochloride (144 mg) and4-diethylaminopyridine (30 mg). The mixture was stirred at ambienttemperature for 18 hours and diluted with dichloromethane. The solutionwas washed with water and brine, dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified by a silicagel column chromatography eluting with 2% methanol in dichloromethane togiveN-[3-(1,2-dimethyl-1H-imidazol-5-yl)-phenyl]-3-methyl-2-trifluoromethyl-1H-indole-7-carboxamide(130 mg,63.1%)

NMR (DMSO-₆, δ): 2.36 (3H, s), 2.44 (3H, s), 3.57 (3H, s), 6.88 (1H, s),7.17 (1H, d, J=8.0 Hz), 7.31 (H, d, J=8.0 Hz), 7.45 (1H, t, J =7.8 Hz),7.82 (1H, d, J=8.0 Hz), 7.9-8.1 (3H, m), 10.50 (1H, s), 11.48 (1H, s)APCI-Mass m/z: 413 (M⁺+1).

EXAMPLE 13

To a suspension of 2,3-dimethylindole-7-carboxylic acid (95 mg) and3-(1,2-dimethylimidazol-5-yl)aniline (94 mg) in dichloromethane (3 ml)were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(144 mg) and 4-dimethylaminopyridine (30 mg). The mixture was stirred atambient temperature for 18 hours and diluted with dichloromethane. Thesolution was washed with water and brine, dried over magnesium sulfateand evaporated under reduced pressure. The residue was purified by asilica gel column chromatography eluting with 3% methanol indichloromethane to giveN-[3-(1,2-dimethyl-1H-imidazol-5-yl)-phenyl]-2,3-dimethyl-lH-indole-7-carboxamide(73 mg, 40.8%).

NMR (DMSO-₆, δ): 2.18 (3H, s), 2.37 (6H, s), 3.57 (3H, s), 6.88 (1H, s),7.06 (1H, d, J=7.6 HZ), 7.15 (1H, d, J=10.1 Hz), 7.44 (1H, d, J=7.9 Hz),7.61 (1H, d, J=7.6 Hz), 7.72 (1H, d, J=7.3 Hz), 7.85 (1H, d, J=8.2 Hz),7.92 (1H, s), 10.30 (1H, s), 10.76 (1H, s) APCI-Mass m/z: 359 (M⁺+1).

EXAMPLE 14

To a suspension of 2-trifluoromethyl-3-methylindole-7-carboxylic acid(122 mg) and 3-(pyrimidin-5-yl)aniline (86 mg) in dichloromethane (3 ml)were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(144 mg) and 4-dimethylaminopyridine (30 mg). The mixture was stirred atambient temperature for 18 hours and diluted with dichloromethane. Thesolution was washed with water and brine, dried over magnesium sulfateand evaporated under reduced pressure. The residue was purified by asilica gel column chromatography eluting with 2% methanol indichloromethane to giveN-[3-(pyrimidin-5-yl)-phenyl]-3-methyl-2-trifluoromethyl-1H-indole-7-carboxamide(106 mg, 53.5%).

NMR (DMSO-d₆, δ): 2.45 (3H, s), 7.31 (1H, t, J=7.7 Hz), 7.4-7.6 (2H, m),7.9-8.1 (3H, m), 8.26 (1H, s), 9.13 (2H, s), 9.23 (1H, s), 10.59 (1H,s), 11.49 (1H, s) APCI-Mass m/z: 397 (M⁺+1).

EXAMPLE 15

To a suspension of 3-(4-fluorophenyl)benzoic acid (151 mg) and3-(1,2-dimethylimidazol-5-yl)aniline (131 mg) in dichloromethane (5 ml)were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(201 mg) and 4-dimethylaminopyridine (43 mg). The mixture was stirred atambient temperature for 18 hours and diluted with dichloromethane. Thesolution was washed with water and brine, dried over magnesium sulfateand evaporated under reduced pressure. The residue was purified by asilica gel column chromatography eluting with 3% methanol indichloromethane to give N-[3-(2,3dimethyl-3H-imidazolyl)-phenyl]-4′-fluoro-biphenyl-3-carboxamide (240mg, 88.9%).

NMR (DMSO-d₆, δ): 2.36(3H, s), 3.57 (3H, s), 6.88 (1H, s), 7.17 (1H, d,J=7.7 Hz), 7.35 (2H, t, J=8.9 Hz), 7.45 (1H, t, J=7.9 Hz), 7.63 (1H, t,J=7.7 Hz), 7.8-8.1 (6H, m), 8.21 (1H, s), 10.43 (1H, s) ESI-Mass m/z:386 (M⁺+1).

Preparation 16(1)

To a suspension of 2-bromo-5-methoxycarbonylthiophene (1.11 g),4-fluorophenylboronic acid (0.91 g) andtetrakis(triphenylphosphine)palladium (289 mg) in 1,2-dimethoxyethane(10 ml) was added aqueous solution of sodium carbonate (2M, 6.5 ml)followed by stirring at 80° C. for 6 hours. The mixture was diluted withdichloromethane and washed with water and brine. The organic layer wasdried over magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by a silica gel column chromatography eluting with30% dichloromethane in n-hexane to give2-methoxycarbonyl-5-(4-fluorophenyl)thiophene (1.16 g, 98.3%).

NMR (CDCl₃, δ): 3.86 (3H, s), 7.32 (2H, t, J=8.8 Hz), 7.59 (1H, d, J=4.0Hz), 7.7-7.9 (3H, m) APCI-Mass m/z : 237 (M⁺+1).

Preparation 16(2)

To a solution of 2-methoxycarbonyl-5-(4-fluorophenyl)thiophene (1.15 g)in methanol (10 ml) and tetrahydrofuran (10 ml) was added an aqueoussolution of sodium hydroxide (1N, 7.3 ml) followed by stirring at 60° C.for 3 hours. To the mixture was added hydrochloric acid (1N, 8 ml). Theresulting precipitate was collected by filtration and dried to give5-(4-fluorophenyl)thiophene-2-carboxylic acid (1.06 g, 98.1%).

NMR (DMSO-d₆, δ): 7.30 (2H, t, J=8.8 Hz), 7.55 (1H, d, J=4.4 Hz),7.7-7.9 (3H, m) ESI-Mass m/z: 223 (M⁺+1).

To a suspension of 5-(4-fluorophenyl)thiophene-2 carboxcylic acid (156mg).and 3-(1,2 dimethylimidazol-5yl)aniline (131 mg) in dichloromethane(5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (201 mg) and 4-dimethylaminopyridine (43 mg). The mixturewas stirred at ambient temperature for 72 hours and diluted withdichloromethane. The solution was washed with water and brine, driedover magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by a silica gel column chromatography eluting with3% methanol in dichloromethane to giveN-[3-(2,3-dimethyl-3H-imidazol4-yl)-phenyl]-5-(4-fluorophenyl)thiophene-2-carboxamide(240 mg, 88.9%).

NMR (DMSO-d₆, δ): 2.36(3H, s), 3.56 (3H, s), 6.88 (1H, s), 7.17 (1H, d,J=7.8 Hz), 7.31 (2H, t, J=8.9 Hz), 7.44 (1H, t, J=7.9 Hz), 7.61 (1H, d,J=4.0 Hz), 7.72 (1H, d, J=8.0 Hz), 8.03 (1H, d, J=4.0Hz), 10.33 (1H, s)APCI-Mass m/z: 392 (M⁺+1).

To a suspension of 2,3-dimethylindole-7-carboxylic acid (95 mg) and1-hydroxybenzotriazole (81 mg) in dichloromethane (3 ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg),and the mixture was stirred for 5 minutes. After adding3-(pyrimidin-5-yl)aniline (94 mg) and 4-dimethylinopyridine (92 mg), themixture was stirred for 24 hours. The mixture was diluted withdichloromethane and washed with water and brine. The organic layer wasdried over magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by a silica gel column chromatography eluting with3% methanol in dichloromethane to giveN-(3-(pyrimidin-5-yl)-phenyl)-2,3-dimethyl-1H-indole-7-carboxamide (117mg, 68.4%).

NMR (DMSO-d₆, δ): 2.19 (3H, s), 2.37 (3H, s), 7.10 (1H, t, J=7.6 Hz),7.5-7.7 (2H, m), 7.63 (1H, d, J=7.7 Hz), 7.77 (1H, d, J=7.7 Hz), 7.9-8.0(1H, m), 8.30 (1H, s), 9.13 (2H, s), 9.23 (1H, s), 10.38 (1H, s), 10.81(1H, s) APCI-Mass m/z: 343 (M⁺+1).

EXAMPLE 18

To a suspension of 9H-carbazole-1-carboxylic acid (112 mg) and3-(1,3,4-triazol-1-yl)aniline (147 mg) in dichloromethane (3 ml) wereadded 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (188mg) and 4-dimethylaminopyridine (43 mg). The mixture was stirred atambient temperature for 24 hours and diluted with dichloromethane. Thesolution was washed with water and brine, dried over magnesium sulfateand evaporated under reduced pressure. The residue was triturated withmethanol. The resulting precipitate was collected by filtration anddried to giveN-(3-([1,2,4]triazol-4-yl)phenyl)-9H-carbazole-1-carboxamide (38 mg,15.4%).

NMR (DMSO-d₆, δ): 7.20 (1H, t, J=7.4 Hz), 7.33 (1H, t, J=7.7 Hz),7.3-7.5 (2H, m), 7.60 (1H, t, J=8.0 Hz), 7.72 (1H, d, J=8.0 Hz), 7.89(1H, d, J=8.4 Hz), 8.1-8.3 (3H, m), 8.40 (1H, d, J=7.5 Hz), 9.09 (2H,s), 10.65 (1H, s), 11.54 (1H, s) APCI-Mass m/z: 354 (M⁺+1).

EXAMPLE 19

To a suspension of 2-trifluoromethyl-3-methylindole-7-carboxylic acid(122 mg) and 4-methyl-3-(pyrimidin-5-yl)aniline (93 mg) indichloromethane (5 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg) and4-dimethylaminopyridine (30 mg). The mixture was stirred at ambienttemperature for 24 hours and diluted with dichloromethane. The solutionwas washed with water and brine, dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified by a silicagel column chromatography eluting with 2% methanol in dichloromethane togiveN-[4-methyl-3-(pyrimidin-5-yl)-phenyl]-3-methyl-2-trifluoromethyl-1H-indole-7-carboxamide(155 mg, 75.6%).

NMR (OMSO-d₆, δ): 2.28 (3H, s), 2.44 (3H, d, J=2.0 Hz), 7.29 (1H, t,J=7.7 Hz), 7.3-7.4 (1H, m), 7.8-8.0 (4H, m), 8.90 (2H, s), 9.24 (1H, s),10.49 (1H, s), 11.44 (1H, s) APCI-Mass m/z: 411 (M⁺+1).

EXAMPLE 20

To a suspension of 2-tifluoromethyl-3-methylidole-7-carboxylic acid (122mg) and 3-(1,2,4-triazol-1-yl)aniline (80 mg) in dichloromethane (5 ml)were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(144 mg) and 4-dimethylaminopyridine (30 mg). The mixture was stirred atambient temperature for 72 hours and diluted with dichloromethane. Thesolution was washed with water and brine, dried over magnesium sulfateand evaporated under reduced pressure. The residue was triturated withmethanol. The resulting precipitate was collected by filtration anddried to giveN-[3-(1,2,4triazol-1-yl)-phenyl]-3-methyl-2-trifluoromethyl-1H-indole-7-carboxamide(97 mg, 50.3%).

NMR (DMSO-d₆, δ): 2.45 (3H, d, J=2.0 Hz), 7.31(1H, t, J=7.7 Hz), 7.5-7.7(2H, m), 7.82 (2H, m), 8.27 (2H, s), 8.51 (1H, s), 9.29 (1H, s), 10.68(1H, s) 11.53 (1H, s) APCI-Mass m/z: 386 (M⁺+1).

Preparation 2(1)

A suspension of 5-bromopyrimidine(1.52 g),2-methylphenylboronic acid(1.43 g), sodium carbonate (3.04 g) and 10% palladium on charcoal (50%wet, 0.85 g) was refluxed for 24 hours. The mixture was filtered and thefiltrate was concentrated under reduced pressure. To the residue ethylacetate was added and the mixture was washed with water and brine. Theseparated organic layer was dried over magnesium sulfate and evaporatedunder pressure to give 5-(2-methylphenyl)pyrimidine (1.61 g, 98.7%).

NMR (DMSO-d₆, δ): 2.27 (3H, s), 7.3-7.5 (4H, m), 8.87 (2H, s), 9.21 (1H,s) APCI-Mass m/z: 171 (M⁺+1).

Preparation 21(2)

To a suspension of 5-(2-methylphenylpyrimidine (0.85 g) in concentratedsulfuric acid (10 ml) was portionwise added potassium nitrate (556 mg)at 5° C. The mixture was stirred at 5° C. for 30 minutes and poured intocrushed ice. The pH of the mixture was adjusted to 8.0 with an aqueoussodium hydroxide solution (4N) and extracted with ethyl acetate. Theorganic layer was washed with water twice and brine, dried overmagnesium sulfate and evaporated under reduced pressure.

The residue was triturated with methanol. The resulting precipitate wascollected by filtration, washed with methanol and dried to give5-(2-methyl-5-nitrophenyl)pyrimidine (662 mg,61.3%).

NMR (DMSO-d₆, δ): 2.38 (3H, s), 7.68 (1H, d. J=8.2 Hz), 8.2-8,4 (2H, m),8.96 (2H, s), 9.28 (1H, s) APCI-Mass m/z 216 (M⁺+1).

Preparation 21(3)

A suspension of 5-(2-methyl-5-nitrophenyl)pyrimidine (0.431 g) intetrahydrofuran (4 ml) and methanol (4 ml) was hydrogenated overpalladium on carbon (10% w/w, 50% wet, 129 mg) under hydrogen atmospherefor 2 hours. The catalyst was filtered off, and the filtrate wasevaporated under reduced pressure to give5-(5-amino-2-methylphenyl)pyrimidine (370 mg, 99.7%).

NMR (DMSO-₆, δ): 2.07 (3H, s), 5.05 (2H, s), 6.48 (1H, d, J=2.4 Hz),6.58 (1H, dd, J=8.0 Hz, 2.4 Hz), 6.99 (1H, d, J=8.0 Hz), 8.78 (2H, s),9.16 (1H, s) APCI-Mass m/z: 186 (M⁺+1).

EXAMPLE 21

To a suspension of 4-methyl-3-(pyrimidin-5-yl)aniline (0.111 g) andpyridine (0.15 ml) in dichloromethane (2 ml) was dropwise added asolution of the fluorene-1-carbonyl chloride (0.137 g) indichloromethane (2 ml) followed by stirring for 2 hours. The mixture wasdiluted with dichloromethane and washed with an aqueous solution ofsodium hydrogen carbonate and brine. The separated organic layer wasdried over sodium sulfate and evaporated under reduced pressure. Theresidue was triturated with methanol. The resulting solid was collectedby filtration to giveN-(4-methyl-3-(pyrimidin-5-yl)-phenyl)-9H-fluorene-1-carboxamide (0.167g, 73.9%)

NMR (DMSO-d₆, δ): 2.25 (3H, s), 4.20 (2H, s), 7.3-7.5 (2H, m), 7.5-7.7(2H, m), 7.7-7.9 (2H. m), 7.97 (1H, d, J=6.5 Hz), 8.11 (1H, d, J=7.1Hz), 8.90 (2H, s), 9.24 (1H, s), 10.41 (1H, s) APCI-Mass m/z: 378(M⁺+1).

EXAMPLE 22

To a suspension of 9H-carbazole-1-carboxylic acid (148 mg) and1-hydroxybenzotriazole (130 mg) in dichloromethane (3 ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (201 mg) andthe mixture was stirred for 5 minutes. After adding4-methyl-3-(pyrimidin-5-yl)aniline (130 mg) and 4-dimethylaminopyridine(128 mg), the mixture was stirred for 24 hours. The mixture was dilutedwith dichloromethane and washed with water and brine. The organic layerwas dried over magnesium sulfate and evaporated under reduced pressure.The residue was purified by a silica gel column chromatography elutingwith 2% methanol in dichloromethane to giveN-(4-methyl-3-(pyrimidin-5-yl)-phenyl)-9H-carbazole-1-carboxamide (140mg, 52.8%).

NMR (DMSO-d₆, δ): 2.28 (3H, s), 7.20 (1H, t, J=7.4 Hz), 7.31 (1H, t,J=7.8 Hz), 7.3-7.5 (2H, m), 7.70 (1H, d, J=8.0 Hz), 7.86 (1H, d , J=8.2Hz), 7.95 (1H, d, J=2.0 Hz), 8.15 (2H, t, J=7.4 Hz), 8.37 (1H, d, J=7.6Hz), 8.93 (2H, s), 9.25 (1H, s), 10.47 (1H, s), 11.52 (1H, s) APCI-Massm/z: 379 (M⁺+1).

Preparation 23

To a suspension of 2,2′-bithiophene (1.0 g) in tetrahydrofuran (10 ml)was added a solution of n-butyl lithium in n-hexane (1.54 M, 4.3 ml) at−25° C. under nitrogen atmosphere. The mixture was stirred at −60° C.for 30 minutes. To the solution dry-ice (1.0 g) was added and themixture was stirred at ambient temperature for 30 minutes. To theresultant suspension hydrochloric acid (1N, 10 ml) and ethyl acetatewere added. The separated organic layer was washed with brine, driedover magnesium sulfate and evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether. The resulting precipitatewas collected by filtration, washed with diisopropyl ether and dried togive [2,2′]bithiophenyl-5-carboxylic acid (952 mg, 75.6%).

NMR (DMSO-d₆, δ): 7.14 (1H, t, J=4.3 Hz), 7.35 (1H, d, J=3.8 Hz),7.4-7.8 (3H, m), 12.5-13.5 (1H, broad s) APCI-Mass m/z: 211 (M⁺+1).

EXAMPLE 23

To a suspension of [2,2′]bithiophenyl-5-carboxylic acid (105 mg) and1-hydroxybenzotriazole (81 mg) in dichloromethane (2 ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg) andthe mixture was stirred for 15 minutes. After adding3-(1,2-dimethylimidazol-5-yl)aniline (94 mg) and 4-dimethylaminopyridine(92 mg), the mixture was stirred for 24 hours. The mixture was dilutedwith dichloromethane and washed with water and brine. The mixture wasdried over magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by a silica gel column chromatography eluting with3% methanol in dichloromethane to giveN-[3-(2,3-dimethyl-3H-imidazol-4-yl)-phenyl]-[2,2′]bithiophenyl-5-carboxamide(117 mg, 61.6%).

NMR DMSO-d₆, δ): 2.36(3H, s), 3.54 (3H, s), 6.88 (1H, s), 7.1-7.2 (2H,m), 7.4-7.6 (3H, m), 7.62 (1H, dd, J=5.1 Hz, 1.1 Hz), 7.7-7.9 (2H, m),7.99 (1H, d, J=4.0 Hz), 10.33 (1H, s) APCI-Mass m/z: 380 (M⁺+1).

EXAMPLE 24

N-(3-(Imidazol-1-yl)phenyl)-1-phenylpyrrole-3-carboxamide was preparedin a manner Far to Example 12.

mp: 100-103° C. (diisopropyl ether/ethyl acetate) IR (KBr, ν): 1645 cm⁻¹NMR (DMSO-d₆, δ): 6.88 (1H, s), 7.13 (1H, s), 7.30-7.80 (10H, m), 8.04(1H, s), 8.10-8.20 (2H, m), 9.89 (1H, s). Mass m/z: 329 (M⁺+1).

To 2-phenylthiazole-4-carboxylic acid (70 mg) in 5 mL benzene was addedthionyl chloride(0.075 mL) at room temperature. The mixture was heatedunder reflux for an hour The mixture was cooled and evaporated underreduced pressure. To the mixture added was dichloromethane (10 ml)followed by 3-(imidazol-1-yl)aniline (54 mg) and triethylamine (0.1 ml).The mixture was stirred at room temperature for an hour. The mixture waswashed with a saturated aqueous sodium bicarbonate solution, dried withsodium sulfate and evaporated. The residue was recrystallized fromdiisopropyl ether/ethyl acetate to giveN-(3-(imidazol-1-yl)phenyl)-2-phenylthiazole-4-carboxamide.

mp: 131-134° C. IR (nujol, ν): 1665 cm⁻¹ NMR (DMSO-d₆, δ): 7.14 (1H, s),7.42 (1H, d, J=9 Hz), 7.45-7.60 (4H, m), 7.72 (1H, s), 7.94 (1H, d, J=8Hz), 8.10-8.25 (4H, m), 8.54 (1H, s), 10.41 (1H,s) Mass m/z: 347 (M⁺+1).

Preparation 26 (1)

To a suspension of m-nitroaniline (2.0 g), phosphoric acid (1.67 ml),butane-2,3-dione (1.27 ml) and an aqueous solution of formaldehyde (35%w/w, 1.24 ml) in water (15 ml) was added an aqueous solution of ammoniumchloride (5M, 6 ml) dropwise at 100° C. After stirring for 2 hours at100° C., the mixture was poured into an aqueous saturated sodiumhydrogen carbonate solution. The mixture was extracted with ethylacetate. The separated organic layer was washed with water and brine,dried over magnesium sulfate and evaporated under reduced pressure. Theresidue was purified with a silica gel column chromatography elutingwith 0-3% methanol/dichloromethane to give4,5-dimethyl-1-(3-nitrophenyl)imidazole (135 mg, 4.3%).

APCI-mass m/z: 218 (M⁺+1) NMR (DMSO-d₆, δ); 2.12 (3H, s), 7.7-7.9 (3H,m), 8.23 (1H, t, J=2.1 Hz), 8.28 (1H, dd, J=1.5 Hz, 8.0 Hz).

Preparation 26 (2)

A suspension of 4,5-dimethyl-1-(3-nitrophenyl)imidazole (130 mg) inmethanol (2 ml) and tetrahydrofuran (2 ml) was hydrogenated overpalladium on carbon (10% w/w, 50% wet, 50 mg) under hydrogen atmospherefor 3 hours. The catalyst was filtered off, and the filtrate wasevaporated under reduced pressure to give3-(4,5-dimethyl-imidazol-1-yl)aniline (110 mg, 98.2%).

APCI-Mass 188 (M⁺+1) NMR (DMSO-d₆, δ) ; 2.05 (3H, s), 2.08 (3H, s), 5.39(2H, s), 6.43(1H, d, J=7.6 Hz), 6.48 (1H, s), 6.60 (1H, d, J=8.1 Hz),7.12 (1H, t, J=8.0 Hz), 7.52 (1H, s).

Preparation 26 (3)

To a suspension of N-formyl-3-nitroaniline (831 mg) and potassiumcarbonate (830 mg) in N,N-dimethylformamide (5 ml) was added2-bromo-3-butanone (906 mg), and the mixture was stirred for 72 hours.The mixture was diluted with ethyl acetate and washed with water andbrine. The mixture was dried over magnesium sulfate and evaporated togive N-(1-methyl-2-oxo-propyl)-N-(3-nitrophenyl)formamide (1.18 g,100%).

APCI-Mass m/z :237 (M⁺+1) NMR (DMSO-d₆, δ); 1.35 (3H, d, J=7.1 Hz), 2.18(3H, s), 4.79 (1H, q, J=7.1 Hz);,7.74 (1H, t, J=8.2 Hz), 7.83 (1H, d,J=8.2 Hz), 8.1-8.2 (2H, m), 8.48 (1H, s)

Preparation 26 (4)

A suspension of N-(1-methyl-2-oxo-propyl)-N-(3-nitrophenyl)formamide(1.17 g), ammonium acetate (3.82 g) and acetic acid (1 ml) in xylene (20ml) was refluxed for 2 hours. After adding ethyl acetate and an aqueoussolution of sodium hydroxide (1N, 100 ml), the mixture was stirred for10 minutes. The separated aqueous layer was extracted with ethylacetate. The combined organic layers were washed with water and brine,dried over magnesium sulfate and evaporated under reduced pressure. Theresidue was purified with a silica gel column chromatography elutingwith 1-3% unethanol/dichloromethane to give4,5-dimethyl-1-(3-nitrophenyl)imidazole (0.79 g, 73.1%).

APCI-Mass m/z :218 (M⁺+1) NMR (DMSO-d₆) δ; 2.13 (6H, s), 7.7-8.0 (3H,m), 8.23 (1H, t, J=2.1 Hz), 8.28 (1H, dd, J=1.5 Hz, 8.0 Hz).

EXAMPLE 26

To a suspension of 9H-carbazole-1-carboxylic acid (116 mg) and3-(4,5dimethylimidazol-1-yl)aniline (103 mg) in dichloromethane (5 ml)were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(158 mg) and 4-dimethylaminopyridine (101 mg), and the mixture wasstirred for 20 hours. The mixture was diluted with dichloromethane andwashed with water and brine. The mixture was dried over magnesiumsulfate and evaporated under reduced pressure. After trituration withmethanol, the residue was collected by filtration and dried to giveN-[3-(4,5-dimethylimidazol-1-yl)-phenyl]-9H-carbazole-1-carboxamide (86mg, 41.1%.

APCI-mass m/z: 381 (M⁺+1) NMR (DMSO-d₆) δ; 2.14 (6H, s), 7.1-7.3 (2H,m), 7.32 (1H, t, J=7.6 Hz), 7.42 (1H, t, J=7.3 HZ), 7.55 (1H, t, J=8.0Hz), 7.66 (1H, s), 7.70 (1H, d, J=8.0 Hz), 7.92 (1H, d, J=8.0 Hz), 8.00(1H, s), 8.12 (1H, d, J=7.6 Hz), 8.18 (1H, d, J=7.6 Hz), 8.40 (1H, d,J=7.6 Hz), 10.60 (1H, s), 11.50 (1H, s).

Preparation 27(1)

To a suspension of N-formyl-3-nitroaniline (1.0 g) inN,N-dimethylformamide (10 ml) was added sodium hydride (60% dispersionin mineral oil, 264 mg), and the mixture was stirred for 20 minutesunder nitrogen atmosphere. After a solution of 1-chloropropan-2-one(0.573 ml) in N,N-dimethylformamide (5 ml) was added dropwise to themixture, the mixture was stirred for 2 hours and diluted with ethylacetate and water. The separated organic layer was washed with brine,dried over magnesium sulfate and evaporated under reduced pressure. Theresidue was purified with a silica gel column chromatography elutingwith 2% methanol in dichloromethane to giveN-(3-nitrophenyl)-N-(2-oxo-propyl)-formamide (280 mg, 21.0%).

APCI-Mass m/z : 223 (M⁺+1) NMR (DMSO-d₆, δ) ; 2.19 (3H, s), 4.78 (2H,s), 7.6-7.8 (2H, m), 8.1-8.2 (2H, m), 8.73 (1H,s).

Preparation 27 (2)

A suspension of N-(3-nitrophenyl)-N-(2-oxo-propyl)-formamide (265 mg),ammonium acetate (919 mg) and acetic acid (0.3 ml) in xylene (5 ml) wasrefluxed for 2.5 hours and then evaporated under reduced pressure. Tothe residue were added ethyl acetate and an aqueous solution of sodiumhydroxide (1N, 25 ml), and the mixture was stirred for 10 minutes. Theseparated organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated to give4-methyl-1-(3-nitrophenyl)imidazole (203 mg, 83.9%).

APCI-Mass m/z :204 (M⁺+1) NMR (DMSO-d₆, δ); 2.17 (3H, s), 7.65 (1H, s),7.78 (1H, t, J=8.2 Hz), 8.1˜8.2 (2H, m), 8.36 (1H, d, J=3.1 Hz), 8.44(1H, t, J=2.2 Hz).

Preparation 27 (3)

A suspension of 4-methyl-1-(3-nitrophenyl)imidazole (198 mg) in methanol(2 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 100mg) under hydrogen atmosphere for 2 hours. After the catalyst wasfiltered off, the filtrate was evaporated under reduced pressure to give3-(4-methyl-imidazolyl)aniline (162 mg, 95.9%).

APCI-Mass m/z: 174 (M⁺+1) NMR (DMSO-d₆, δ); 2.14 (3H, s), 5.35 (2H, s),6.51 (1H, d, J=7.0 Hz), 6.6-6.8 (2H, m), 7.09 (1H, t, J=7.8 Hz), 7.23(1H, s), 7.91 (1H, d, J=1.2 Hz).

EXAMPLE 27

To a suspension of 9H-fluorene-1-carboxylic acid (79 mg) and3-(4-methylimidazol-1-yl)aniline (65 mg) in dichloromethane (2 ml) wasadded 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (101mg) and 4-dimethylaminopyridine (23 mg), and the mire was stirred for 24hours. The mix e was diluted with dichloromethane, washed with water andbrine. The mixture was dried over magnesium sulfate and evaporated underreduced pressure. The residue was triturated with methanol, and theinsoluble material was collected by filtration and dried to giveN-[3-(4-methylimidazol-1-yl)-phenyl]-9H-fluorene-1-carboxamide (40 mg,29.2%).

APCI-mass m/z: 366 (M⁺+1) NMR (DMSO-d₆) δ; 2.18 (3H, s), 4.21 (2H, s),7.3-7.8 (9H, m), 7.98 (1H, d, J=6.5 Hz), 8.0-8.1 (2H, m), 8.13 (1H, d,J=7.3 Hz), 10.53 (1H, s).

EXAMPLE 28

To a suspension of 9H-fluorene-1-carboxylic acid (106 mg) and3-(4,5-dimethylimidazol-1-yl)aniline (94 mg) in dichloromethane (2 ml)were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(135 mg) and 4-dimethylaminopyridine (31 mg), and the mixture wasstirred for 24 hours. The mixture was diluted with dichloromethane andwashed with water and brine. The mixture was dried over magnesiumsulfate and evaporated under reduced pressure. The residue wastriturated with methanol, and the insoluble material was collected byfiltration and dried to giveN-[3-(4,5-dimethylimidazol-1-yl)-phenyl]-9H-fluorene-1-carboxamide (123mg, 64.7%).

APCI-mass m/z: 380 (M⁺+1) NMR (DMSO-d₆, δ); 2.13 (6H, s), 4.20 (2H, s),7.15 (1H, d, J=8.4 Hz), 7.3-7.5 (6H, m), 7.75 (1H, d, J=6.9 Hz), 7.8-7.9(2H, m), 7.98 (1H, d, J=6.6 Hz), 8.13 (1H, d, J=6.9 Hz), 10.57 (1H, s):

EXAMPLE 29

To a suspension of 3-(2-thienyl)benzoic acid (103 mg) and3-(4,5-dimethylimidazol-1-yl)aniline (94 mg) in dichloromethane (2 ml)were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(135 mg) and 4-dimethylaminopyridine (31 mg), and the mixture wasstirred for 24 hours. The mixture was diluted with dichloromethane andwashed with water and brine. The mixture was dried over magnesiumsulfate and evaporated under reduced pressure. The residue wastriturated with methanol, and the insoluble material was collected byfiltration and dried to giveN-[3-(4,5-dimethylimidazol-1-yl)-phenyl]-3-(2-thienyl)benzamide (117 mg,62.6%).

APCI-mass m/z: 374 (M⁺+1) NMR DMSO-d₆, δ) ; 2.12 (6H, s), 7.1-7.3 (2H,m), 7.52 (1H, t, J=8.0 Hz), 7.6-7.8 (4H, m), 7.8-8.0 (4H, m), 8.18 (1H,s), 10.57 (1H, s).

Preparation 30 (1)

To a solution of N-(4fluorophenyl)-2,2-dimethylpropionamide (195 mg) intetrahydrofuran (2 ml) was added a solution of n-butyl lithium inn-hexane (1.54M, 1.5 ml) dropwise at 0° C. under nitrogen atmosphere,and the mixture was stirred for 2 hours at 0° C. To the reaction mixturewas added triisopropyl borate (0.692 ml) at −40° C., and the mixture wasstirred for 30 minutes at ambient temperature. To the mixture was added1N-hydrochloric acid (3 ml), and the mixture was diluted with ethylacetate and water. The separated organic layer was washed with brine,dried over magnesium sulfate and evaporated under reduced pressure. Tothe residue were added methyl 3-bromo-2-fluorobenzoate (117 mg),tetrakis(triphenylphosphine)palladium (29 mg), an aqueous solution ofsodium carbonate (2M, 2 ml) and 1,2-dimethoxyethane (5 ml). Theresulting mixture was stirred under nitrogen atmosphere for 48 hours at75° C., and diluted with ethyl acetate and water. The separated organiclayer was washed with brine, dried over magnesium sulfate and evaporatedunder reduced pressure. The residue was purified with a silica gelcolumn chromatography eluting with 20% ethyl acetate/n-hexane to give2′-(2,2-dimethylpropionamido)-2,5′-difluoro-biphenyl-3-carboxylic acidmethyl ester (106 mg, 60.9%).

APCI-mass m/z: 348 (M⁺+1) NMR (DMSO-d₆, δ); 0.96 (9H, s), 3.85 (3H, s),7.2-7.4 (4H, m), 7.52 (1H, dt, J=2.0 Hz, 7.1 Hz), 7.86 (1H, dt, J=1.9Hz, 7.3 Hz), 8.92 (1H, s).

Preparation 30 (2)

A mixture of2′-(2,2-dimethyl-propionamido)-2,5′-difluoro-biphenyl-3-carboxylic acidmethyl ester (92 mg) and pyridinium chloride (3.0 g) was stirred for 3hours at 200° C., and then poured into ice-water. The suspension wasstirred for 10 minutes. The precipitate was collected by filtration,washed with water and dried to give 6-fluoro-9H-carbazole-1-carboxylicacid (46 mg, 76.7%).

ESl-mass m/z: 228 (M⁺+1) NMR (DMSO-d₆, δ) ; 7.2-7.4 (2H, m), 7.73 (1H,dd, J=4.6 Hz, 8.9 Hz), 8.0-8.1 (2H, m), 8.42 (1H, d, J=7.3 Hz), 11.38(1H, s), 13.19 (1H, broad s).

Preparation 30 (3)

A suspension of 3-bromonitrobenzene (20.2 g), 1,2-dimethyl-1H-imidazole(19.2 g), palladium acetate (1.12 g) and potassium carbonate (27.6 g) inN,N-dimethylformamide (500 ml) was stirred under nitrogen atmosphere for24 hours at 140° C., and evaporated under reduced pressure. The residuewas diluted with ethyl acetate and washed with water three times. Theseparated organic layer was washed with brine, dried over magnesiumsulfate and evaporated under reduced pressure to give3-(1,2-dimethyl-imidazol-1-yl)nitrobenzene (19.2 g).

APCI-Mass m/z: 218 (M⁺+1) NMR (DMSO-d₆, δ) ; 2.37(3H, s), 3.58 (3H, s),7.09 (1H, s), 7.74 (1H, t, J=7.9 Hz), 7.91 (1H, d, J=7.7 Hz), 8.1-8.3(2H, m).

Preparation 30 (4)

A suspension of 3-(1,2-dimethyl-1H-imidazol-5-yl)nitrobenzene (19.2 g)in methanol (200 ml) was hydrogenated over palladium on carbon (10% w/w,50% wet, 5 g) under hydrogen atmosphere for 10 hours. After the catalystwas filtered off, the filtrate was evaporated under reduced pressure.The residue was triturated with ethyl acetate and diisopropyl ether togive 3-(1,2-dimethyl-imidazol-5-yl)aniline (14.65 g).

APCI-Mass m/z: 188 (M⁺+1) NMR (DMSO-d₆, δ); 2.32 (3H, s), 3.49 (3H, s),5.16 (2H, s), 6.5-6.7 (3H, m), 6.73 (1H, s), 7.07 (1H, t, J=7.7 Hz).

EXAMPLE 30

To a suspension of 6-fluoro-9H-carbazole-1-carboxylic acid (37 mg) and3-(1,2-dimethylimidazol-5-yl)aniline (43 mg) in dichloromethane (1 ml)were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(53 mg) and 4-dimethylaminopyridine (11 mg), and the mixture was stirredfor 40 hours. The mixture was diluted with dichloromethane and washedwith water and brine. The mixture was dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified with asilica gel column chromatography eluting with 2-3%methanol/dichloromethane to giveN-[3-(1,2-dimethylimidazol-5-yl)-phenyl]-6-fluoro-9H-carbazole-1-carboxamide(38 mg, 51.4%).

APCI-mass m/z: 399 (M⁺+1) NMR (DMSO-d₆, δ) ; 2.37(3H, s), 3.59 (3H, s),6.90 (1H, s), 7.2-7.4 (3H, m), 7.47 (1H, t, J=7.9 Hz), 7.70 (1H, dd,J=4.6 Hz, 8.9 Hz), 7.88 (1H, d, J=8.1 Hz), 7.95 (1H, s), 8.03 (1H, d,J=2.5 Hz, 9.4 Hz), 8.14 (1H, d, J=7.2 Hz), 8.40 (1H, d, J=7.6 Hz), 10.48(1H, s), 11.55 (1H, s).

Preparation 31 (1)

To a suspension of 2-hydrazinobenzoic acid hydrochloride (2.0 g) inacetic acid (8 ml) was added dropwise a solution of 2-butanone (0.9 ml)in acetic acid (2 ml), and the resultant mixture was heated at 80° C.for one hour. After 6N-hydrochloric acid (8 ml) was added to thereaction mixture, the mixture was heated at 100° C. for 5 hours. Themixture was diluted with water (18 ml), and allowed to cool to 40° C.The resultant precipitate was collected by filtration, washed with asmall amount of diisopropyl ether and dried in vacuo to give2,3-dimethyl-1H-indole-7-carboxylic acid (0.78 g).

APCI-mass m/z: 190 (M⁺+1) NMR (DMSO-d₆, δ); 2.17(3H, s), 2.36 (3H, s),7.02 (1H, t, d=7.6 Hz), 7.63 (2H, d, d=7.6 Hz), 10.55 (1H, brs), 12.82(1H, brs).

EXAMPLE 31

To a suspension of 2,3-dimethyl-1H-indole-7-carboxylic acid (95 mg) and3-(4,5-dimethylimidazol-1-yl)aniline (94 mg) in dichloromethane (2 ml)were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(135 mg) and 4-dimethylaminopyridine (31 mg), and the mixture wasstirred for 12 hours. The mixture was diluted with dichloromethane andwashed with water and brine. The mixture was dried over magnesiumsulfate and evaporated under reduced pressure. The residue wastriturated with dichloromethane, and the insoluble material wascollected by filtration and dried to giveN-[3-(4,5-dimethyl-imidazol-1-yl)-phenyl]-2,3-dimethyl-1H-indole-7-carboxamide(77 mg, 43.0%).

APCI-mass m/z: 359 (M⁺+1) NMR (DMSO-d₆, δ); 2.12 (6H, s), 2.19 (3H, s),2.36 (3H, s), 7.07 (1H, d, J=7.6 Hz), 7.1-7.2 (1H, m), 7.51 (1H, t,J=8.0 Hz), 7.62 (1H, d, J=7.6 Hz), 7.64 (1H, s), 7.72 (1H, d, J=7.4 Hz),7.88 (1H, d, J=8.0 Hz), 7.96 (1H, t, J=2.0 Hz), 10.42 (1H, s), 10.77(1H, s).

EXAMPLE 32

To a suspension of 6-fluoro-9H-carbazole-1-carboxylic acid (70 mg) and3-(4,5-dimethylimidazol-1-yl)aniline (60 mg) in dichloromethane (2 ml)were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(88 mg) and 4-dimethylaminopyridine (19 mg), and the mixture was stirredfor 40 hours. The mixture was diluted with dichloromethane and washedwith water and brine. The mixture was dried over magnesium sulfate andevaporated under reduced pressure. The residue was purified with asilica gel column chromatography eluting with 2-3%methanol/dichloromethane to giveN-[3-(4,5-diethylimidazol-1-yl)-phenyl]-6-fluoro-9H-carbazole-1-carboxamide(65 mg, 53.7%).

APCI-mass m/z: 399 (M⁺+1) NMR (DMSO-d₆, δ); 2.14 (6H, s), 7.17 (1H, d,J=7.9 Hz), 7.3-7.5 (2H, m), 7.55 (1H, t, J=8.0 Hz), 7.6-7.8 (2H, m),7.92 (1H, d, J=8.3 Hz), 8.0-8.1 (2H, m), 8.14 (1H, d, J=7.1 Hz), 8.41(1H, d, J=7.5 Hz), 10.60 (1H, s), 11.56 (1H, s).

EXAMPLE 33

To a suspension of 9H-carbazole-1-carboxylic acid (106 mg) and3-(4-methylimidazol-1-yl)aniline (87 mg) in dichloromethane (5 ml) wereadded 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144mg) and 4-dimethylaminopyridine (31 mg), and the mixture was stirred for40 hours. The mixture was diluted with dichloromethane and washed withwater and brine. The mixture was dried over magnesium sulfate andevaporated under reduced pressure. The residue was triturated withmethanol, and the insoluble material was collected by filtration anddried to giveN-[3-(4-methylimidazol-1-yl)-phenyl]-9H-carbazole-1-carboxamide (68 mg,37.0%).

APCI-mass m/z: 367(m⁺+1) NMR (DMSO-b₆, δ); 2.19 (3H, s), 7.20 (1H, t,J=7.5 Hz), 7.3-7.5 (4H, m), 7.52 (1H, t, J=8.0 Hz), 7.72 (1H, d, J=8.0Hz), 7.80 (1H, d, J=8.4 Hz), 8.09 (1H, d, J=9.2 Hz), 8.2-8.3 (3H, m),8.40 (1H, d, J=7.6 Hz), 10.56 (1H, s), 11.53 (1H, s).

What is claimed is:
 1. A compound of formula (I):

wherein R¹ is a 4-(lower) alkyl-imidazol-1-yl or a 4,5-di(lower)alkyl-imidazol-1-yl group, R² is a hydrogen atom or a lower alkyl group,and R³ is a fluorenyl group, or pharmaceutically acceptable saltsthereof.
 2. A pharmaceutical composition, which has 5-HT antagonismactivity, comprising a compound of claim 1 or its non-toxicpharmaceutically acceptable salt together with pharmaceutical carrier.3. The compound of formula (I) of claim 1, wherein the compound is inthe form of a pharmaceutically acceptable salt.
 4. The compound offormula (I) of claim 3, wherein the compound is in the form of a salt ofan inorganic base, a salt of an organic base, an inorganic additionsalt, an organic carboxylic or sulfonic salt, a salt of a basic oracidic amino acid, or mixtures thereof.
 5. The compound of formula (l)of claim 4, wherein the compound is in the form of a salt of an alkalimetal or a salt of an alkaline earth metal.
 6. The compound of formula(I) of claim 4, wherein the compound is in the form of a triethylaminesalt, a pyridine salt, a picoline salt, an ethanolamine salt, atriethanolamine salt, a dicyclohexylamine salt, or anN,N′-dibenzylethylenediamine salt.
 7. The compound of formula (I) ofclaim 4, wherein the compound is in the form of a hydrochloride salt, ahydrobromide salt, a hydriodide salt, a sulfate salt, or a phosphatesalt.
 8. The compound of formula (I) of claim 4, wherein the compound isin the form of a formate salt, an acetate salt, a trifluoroacetate salt,a maleate salt, a tartrate salt, a methanesulfonate salt, abenzenesulfonate salt, or a p-toluenesulfonate salt.
 9. The compound offormula (I) of claim 7, wherein the compound is in the form of anarginine salt, a aspartate salt, or a glutamate salt.
 10. The compoundof formula (I) of claim 1, wherein R¹ is a lower alkyl group having 1 to6 carbon atoms.
 11. The compound of formula (I) of claim 1, wherein R¹is a lower alkyl group having 1 to 4 carbon atoms.
 12. The compound offormula (I) of claim 1, wherein R¹ is a lower alkyl group selected fromthe group consisting of methyl, ethyl, propyl, isopropyl, butyl,t-butyl, pentyl and hexyl.
 13. The pharmaceutical composition of claim2, wherein the pharmaceutical composition is in the form of a tablet,granule, powder, capsule, solution, suspension, syrup, emulsion orlemonade.
 14. The pharmaceutical composition of claim 2, wherein theamount of the compound of formula (I) is 0.05 to 100 mg.